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Arun V Holden

Publications and source records attributed to Arun V Holden.

16 recordsLinked to original sources
PubMed2006

Heterogeneous three-dimensional anatomical and electrophysiological model of human atria.

Investigating the mechanisms underlying the genesis and conduction of electrical excitation in the atria at physiological and pathological states is of great importance. To provide knowledge concerning the mechanisms of excitation, we constructed a biophysical detailed and anatomically accurate computer model of human atria that incorporates both structural and electrophysiological heterogeneities. The three-dimensional geometry was extracted from the visible female dataset. The sinoatrial node (SAN) and atrium, including crista terminalis (CT), pectinate muscles (PM), appendages (APG) and Bachmann's bundle (BB) were segmented in this work. Fibre orientation in CT, PM and BB was set to local longitudinal direction. Descriptions for all used cell types were based on modifications of the Courtemanche et al. model of a human atrial cell. Maximum conductances of Ito, IKr and ICa,L were modified for PM, CT, APG and atrioventricular ring to reproduce measured action potentials (AP). Pacemaker activity in the human SAN was reproduced by removing IK1, but including If, ICa,T, and gradients of channel conductances as described in previous studies for heterogeneous rabbit SAN. Anisotropic conduction was computed with a monodomain model using the finite element method. The transversal to longitudinal ratio of conductivity for PM, CT and BB was 1:9. Atrial working myocardium (AWM) was set to be isotropic. Simulation of atrial electrophysiology showed initiation of APs in the SAN centre. The excitation spread afterwards to the periphery near to the region of the CT and preferentially towards the atrioventricular region. The excitation extends over the right atrium along PM. Both CT and PM activated the right AWM. Earliest activation of the left atrium was through BB and excitation spread over to the APG. The conduction velocities were 0.6ms-1 for AWM, 1.2ms-1 for CT, 1.6ms-1 for PM and 1.1ms-1 for BB at a rate of 63bpm. The simulations revealed that bundles form dominant pathways for atrial conduction. The preferential conduction towards CT and along PM is comparable with clinical mapping. Repolarization is more homogeneous than excitation due to the heterogeneous distribution of electrophysiological properties and hence the action potential duration.

Action Potentials↗
PubMed2006

Endogenous driving and synchronization in cardiac and uterine virtual tissues: bifurcations and local coupling.

Cardiac and uterine muscle cells and tissue can be either autorhythmic or excitable. These behaviours exchange stability at bifurcations produced by changes in parameters, which if spatially localized can produce an ectopic pacemaking focus. The effects of these parameters on cell dynamics have been identified and quantified using continuation algorithms and by numerical solutions of virtual cells. The ability of a compact pacemaker to drive the surrounding excitable tissues depends on both the size of the pacemaker and the strength of electrotonic coupling between cells within, between, and outside the pacemaking region. We investigate an ectopic pacemaker surrounded by normal excitable tissue. Cell-cell coupling is simulated by the diffusion coefficient for voltage. For uniformly coupled tissues, the behaviour of the hybrid tissue can take one of the three forms: (i) the surrounding tissue electrotonically suppresses the pacemaker; (ii) depressed rate oscillatory activity in the pacemaker but no propagation; and (iii) pacemaker driving propagations into the excitable region. However, real tissues are heterogeneous with spatial changes in cell-cell coupling. In the gravid uterus during early pregnancy, cells are weakly coupled, with the cell-cell coupling increasing during late pregnancy, allowing synchronous contractions during labour. These effects are investigated for a caricature uterine tissue by allowing both excitability and diffusion coefficient to vary stochastically with space, and for cardiac tissues by spatial gradients in the diffusion coefficient.

Action Potentials↗
PubMed2005

Role of up-regulation of IK1 in action potential shortening associated with atrial fibrillation in humans.

OBJECTIVES: Although previous studies in dogs have indicated a minimal role for changes in I(K1) in the shortening of action potential duration (APD) associated with atrial fibrillation (AF), in humans, there is evidence for significant AF-induced up-regulation of this current. In this computer model study, we investigated the relative contributions of the remodeling of I(K1), L-type calcium current, and other remodeled ionic channel currents to AF-induced APD reduction in human atrium. METHODS: Two computer models of electrical activity of human atrial cell were modified by incorporating experimental data of AF-induced changes in human atrial ionic channel conductance and kinetics reported by Bosch et al. (I(CaL), I(to), I(K1), and I(Na)) (AF-1) and Workman et al. (I(CaL), I(to), and I(K1)) (AF-2). The roles and relative importance of individually remodeled ion channels in the APD reduction in human atrium were evaluated by the removal and exclusive methods, in which remodeling of specific currents was omitted, or considered in isolation, in the two models. RESULTS: When tested together, previously reported AF-induced changes in sarcolemmal ion currents result in marked shortening of atrial APD(90). With the AF-1 remodeled parameters, there is a 62% reduction in APD(90) for the Nygren et al. model, and a 68% reduction for the Courtemanche et al. model, which are comparable to experimental results of 60% reduction seen in humans. When tested individually, AF-1-induced changes in I(CaL), I(K1), or I(to) alone result in APD(90) reduction of 20%, 64%, and -10%, respectively, for the Nygren et al. model, and 27%, 40%, and 11.6%, respectively, for the Courtemanche et al. model. With the AF-2 remodeled parameters, there is a 47% reduction in APD(90) for the Nygren et al. model and a 49% reduction for the Courtemanche et al. model, which are also comparable to experimental results of 45% reduction. When tested individually, AF-2-induced changes in I(CaL) or I(K1) alone result in APD(90) reduction of 20% and 40%, respectively, for the Nygren et al. model, and 14% and 21%, respectively, for the Courtemanche et al. model. CONCLUSION: Previously reported changes in L-type Ca(2+) current are insufficient to account for the observed reduction in atrial APD associated with persistent AF. Up-regulation of I(K1) has a greater influence on atrial APD in the human model.

Action Potentials↗
PubMed2005

Dispersion of cardiac action potential duration and the initiation of re-entry: a computational study.

BACKGROUND: The initiation of re-entrant cardiac arrhythmias is associated with increased dispersion of repolarisation, but the details are difficult to investigate either experimentally or clinically. We used a computational model of cardiac tissue to study systematically the association between action potential duration (APD) dispersion and susceptibility to re-entry. METHODS: We simulated a 60 x 60 mm2 D sheet of cardiac ventricular tissue using the Luo-Rudy phase 1 model, with maximal conductance of the K+ channel gKmax set to 0.004 mS mm(-2). Within the central 40 x 40 mm region we introduced square regions with prolonged APD by reducing gKmax to between 0.001 and 0.003 mS mm(-2). We varied (i) the spatial scale of these regions, (ii) the magnitude of gKmax in these regions, and (iii) cell-to-cell coupling. RESULTS: Changing spatial scale from 5 to 20 mm increased APD dispersion from 49 to 102 ms, and the susceptible window from 31 to 86 ms. Decreasing gKmax in regions with prolonged APD from 0.003 to 0.001 mS mm-2 increased APD dispersion from 22 to 70 ms, and the susceptible window from <1 to 56 ms. Decreasing cell-to-cell coupling by changing the diffusion coefficient from 0.2 to 0.05 mm2 ms(-1) increased APD dispersion from 57 to 88 ms, and increased the susceptible window from 41 to 74 ms. CONCLUSION: We found a close association between increased APD dispersion and susceptibility to re-entrant arrhythmias, when APD dispersion is increased by larger spatial scale of heterogeneity, greater electrophysiological heterogeneity, and weaker cell-to-cell coupling.

Action Potentials↗
PubMed2005

Imaging the heart: computer 3-dimensional anatomic models of the heart.

Since the 1960s, models of the action potential in various cardiac cell types have been developed, and since the 1990s, 3-dimensional anatomic (or geometric) models of various cardiac structures have been developed. We are approaching the time when, for one species, we should have a complete set of action potential and anatomic models for the various cardiac tissues and then we will have realized the aim of constructing a "virtual heart" with accurate anatomy and electrophysiology. However, already the two types of model are beginning to be used in tandem to reconstruct the activation sequence of the heart both during sinus rhythm and arrhythmias.

Action Potentials↗
PubMed2004

Filament behavior in a computational model of ventricular fibrillation in the canine heart.

The aim of this paper was to quantify the behavior of filaments in a computational model of re-entrant ventricular fibrillation. We simulated cardiac activation in an anisotropic monodomain with excitation described by the Fenton-Karma model with Beeler-Reuter restitution, and geometry by the Auckland canine ventricle. We initiated re-entry in the left and right ventricular free walls, as well as the septum. The number of filaments increased during the first 1.5 s before reaching a plateau with a mean value of about 36 in each simulation. Most re-entrant filaments were between 10 and 20 mm long. The proportion of filaments touching the epicardial surface was 65%, but most of these were visible for much less than one period of re-entry. This paper shows that useful information about filament dynamics can be gleaned from models of fibrillation in complex geometries, and suggests that the interplay of filament creation and destruction may offer a target for antifibrillatory therapy.

Action Potentials↗
PubMed2003

Effect of regional differences in cardiac cellular electrophysiology on the stability of ventricular arrhythmias: a computational study.

Re-entry is an important mechanism of cardiac arrhythmias. During re-entry a wave of electrical activation repeatedly propagates into recovered tissue, rotating around a rod-like filament. Breakdown of a single re-entrant wave into multiple waves is believed to underlie the transition from ventricular tachycardia to ventricular fibrillation. Several mechanisms of breakup have been identified including the effect of anisotropic conduction in the ventricular wall. Cells in the inner and outer layers of the ventricular wall have different action potential durations (APD), and support re-entrant waves with different periods. The aim of this study was to use a computational approach to study twisting and breakdown in a transmural re-entrant wave spanning these regions, and examine the relative role of this effect and anisotropic conduction. We used a simplified model of action potential conduction in the ventricular wall that we modified so that it supported stable re-entry in an anisotropic model with uniform APD. We first examined the effect of regional differences on breakdown in an isotropic model with transmural differences in APD, and found that twisting of the re-entrant filament resulted in buckling and breakdown during the second cycle of re-entry. We found that breakdown was amplified in the anisotropic model, resulting in complex activation in the region of longest APD. This study shows that regional differences in cardiac electrophysiology are a potentially important mechanism for destabilizing re-entry and may act synergistically with other mechanisms to mediate the transition from ventricular tachycardia to ventricular fibrillation.

Action Potentials↗
PubMed2002

Dynamics and interaction of filaments in a computational model of re-entrant ventricular fibrillation.

Ventricular fibrillation (VF) is a lethal cardiac arrhythmia. Re-entry, in which action potential wavefronts rotate around filaments, is believed to sustain VF. In this study we used a computational model of multiple wavelet fibrillation in the thin-walled right ventricle (10 mm thick) and the thicker walled left ventricle (16 mm thick) to investigate the effect of tissue thickness and initiation protocol on re-entry, and to examine whether filament dynamics and interaction in the model could explain why re-entry is both rarely observed and short-lived in experimental studies that map electrical activation on the heart surface. We found (i) that the density of filaments, the proportion of transmural filaments and the proportion of filaments visible on the model surface were all higher in the 10 mm simulation, (ii) that the initiation protocol influences the rate of filament breakdown but not the number of filaments present after 1 s, and (iii) that although many filaments are visible on the surface of the model, the majority are visible for less than one rotation. This study shows that tissue thickness, geometry and initiation protocol influence electrical activation during VF, and that the rapid motion and interaction of filaments result in transient appearance of surface re-entry.

Anisotropy↗
PubMed2002

A method to quantify the dynamics and complexity of re-entry in computational models of ventricular fibrillation.

Ventricular fibrillation is a deadly cardiac arrhythmia. There is evidence that electrical activity in cardiac tissue is sustained during fibrillation by re-entrant waves that rotate around filaments. In this paper we develop a method for identifying and tracking filaments in a computational model of ventricular fibrillation. This method identifies the birth, death, bifurcation and amalgamation of filaments and these events are summarized on a directed graph. The approach described in this study provides ways to quantify the complex patterns of electrical activity seen in computational models of fibrillation, to relate the behaviour of computational models to experimental data and thus to gain insights into the underlying mechanisms of this dangerous arrhythmia.

Anisotropy↗
PubMed2002

Analysis of the chronotropic effect of acetylcholine on sinoatrial node cells.

INTRODUCTION: The ionic basis underlying the negative chronotropic effect of acetylcholine (ACh) on sinoatrial (SA) node cells is unresolved and controversial. In the present study, mathematical modeling was used to address this issue. METHODS AND RESULTS: The known concentration-dependent effects of ACh on iK,ACh, iCa,L, and i(f) were introduced into models of rabbit central and peripheral SA node cells. In the central and peripheral models, 9 x 10(-8) and 14 x 10(-8) M ACh, respectively, caused a 50% decrease in pacemaking rate, whereas in rabbit SA node to approximately 7.4 x 10(-8) M ACh caused such a decrease. In the models, iK,ACh was primarily responsible for the decrease and actions of ACh on iCa,L or i(f) alone caused a negligible effect. Although the inhibition of i(f) did not directly contribute to the chronotropic effect, it was indirectly important, because it minimized the opposition by i(f ) to the decrease of rate caused by activation of iK,ACh. The central model was more sensitive to ACh than the peripheral model. CONCLUSION: The chronotropic effect of ACh is principally the result of activation of iK,ACh, and inhibition of iCa,L plays little or no role. Inhibition of i(f) and possible inhibition of ib,Na play an important facilitative role by reducing the ability of i(f) and ib,Na to curtail the chronotropic effect caused by activation of iK,ACh.

Acetylcholine↗
PubMed2002

Sustained inward current and pacemaker activity of mammalian sinoatrial node.

INTRODUCTION: A novel sustained inward Na+ current i(sv), which sensitive to Ca2+-antagonists and potentiated by beta-adrenergic stimulation, has been described in pacemaker cells of rabbit, guinea pig, and rat sinoatrial node, as well as rabbit AV node. Although i(st) has been suggested to be an important pacemaker current, this has never been tested experimentally because of the lack of a specific blocker. In this study, we address the role of i(st) in the pacemaker activity of the sinoatrial node cell using computer models. METHODS AND RESULTS: The newly developed models of Zhang et al. for peripheral and central rabbit sinoatrial node cells and models of Noble and Noble, Demir et al., Wilders et al., and Dokos et al. for typical rabbit sinoatrial node cells were modified to incorporate equations for i(st). The conductance g(st) was chosen to give a current density-voltage relationship consistent with experimental data. In the models of Zhang et al. (periphery), Noble and Noble, and Dokos et al., in which i(st) was smaller or about the same amplitude as other inward currents, i(st) increased the pacemaking rate by 0.6%, 2.2%, and 0.8%, respectively. In the models of Zhang et al. (center), Demir et al., and Wilders et al., in which i(st) was larger than some other inward ionic currents, i(st) increased the pacemaking rate by 7%, 20%, and 14%, respectively. CONCLUSION: i(st) has the potential to be a regulator of pacemaker activity, although its importance will depend on the amplitude of i(st) relative to the amplitude of other inward currents involved in pacemaker activity.

Action Potentials↗
PubMed2002

Computational framework for simulating the mechanisms and ECG of re-entrant ventricular fibrillation.

Ventricular arrhythmias remain an important cause of morbidity and mortality in the Western world. Although the underlying mechanisms of these arrhythmias can be studied experimentally, these investigations are in general limited to mapping electrical activity on the heart surface. Computational models of action potential propagation offer a potentially powerful way to study electrical activation and arrhythmias, but current models are not easy to link to the clinical environment. In this paper, we describe a framework for computing action potential propagation in which the geometry, electrophysiology and regional properties of ventricular myocardium can be specified so that, for example, different models for cardiac cellular electrophysiology can be used. We have computed action potential propagation during both normal beats and re-entry in an anatomically accurate model of ventricular geometry. By computing the resultant electric current flow in the torso we have also generated simulated ECG signals that result from specific activation patterns in the ventricular model. Models can be powerful tools for explaining observations, and this approach is able to provide a direct link between the different configurations of re-entry observed in computational and experimental studies, and the ECG signals observed in patients.

Action Potentials↗
PubMedDate not supplied

Propagation of normal beats and re-entry in a computational model of ventricular cardiac tissue with regional differences in action potential shape and duration.

There is substantial experimental evidence from studies using both intact tissue and isolated single cells to support the existence of different cell types within the ventricular wall of the heart, each possessing different electrical properties. However other studies have failed to find these differences, and instead support the idea that electrical coupling in vivo between regions with different cell types smoothes out differences in action potential shape and duration. In this study we have used a computational model of electrical activation in heterogenous 2D and 3D cardiac tissue to investigate the propagation of both normal beats and arrhythmias. We used the Luo-Rudy dynamic model for guinea pig ventricular cells, with simplified Ca2+ handling and transmural heterogeneity in IKs and Ito. With normal cell-to-cell coupling, a layer of M cells was not necessary for the formation of an upright T wave in the simulated electrocardiogram, and the amplitude and configuration of the T wave was not greatly affected by the thickness and configuration of the M cell layer. Transmural gradients in repolarisation pushed re-entrant waves with an intramural filament towards either the base or the apex of the ventricles, and caused transient break up of re-entry with a transmural filament.

Action Potentials↗
PubMedDate not supplied

The sensitivity of the heart to static magnetic fields.

Static magnetic fields induce flow potentials in arterial flows in and around the heart, that have been detected as distortions in the ECG. The resultant currents flowing through the myocardium could alter the rate or rhythm of the heart. No such changes have been seen in animal experiments, or with humans, in static fields up to 8 T. The possible effects of such currents induced by fields larger than 8 T on cardiac pacemaker rate, and arrhythmogenesis are reviewed, using virtual cardiac tissues-computational models of cardiac electrophysiology. Arrhythmogenesis can be by the initiation of ectopic beats, or by re-entry, whose probability of occurrence is increased by any increase in the electrical heterogeneity, in particular, the action potential duration heterogeneity of the ventricle. Focal ectopic activity would be readily detectable, but since re-entrant arrhythmias are very rare events, even a large increase in their probability of occurrence still leaves them unlikely to be observed. Both of these two arrhythmogenic mechanisms would show a steep sigmoidal, or threshold dependence on induced current intensity, with the threshold for increasing the vulnerability to re-entry less than the threshold for initiating activity. Failure to observe them at fields less than 8 T provides only a lower bound for any threshold for arrhythmogenesis.

Action Potentials↗